1. Field of the Invention
The present invention relates to salts of cefamandole, a member of the cephalosporin family of antibiotics. This invention also relates to compositions containing the salts, and to methods of making and using those compositions. The salts have a very limited aqueous solubility, and therefore can be formulated in aqueous compositions having long term stability.
2. Discussion of Related Art
Cefamandole is a semisynthetic cephalosporin antibiotic presently in use as a parenterally administered drug. This drug is described in U.S. Pat. No. 3,641,021. During the developmental phase of this drug, it was found that cefamandole is very difficult to crystallize. Subsequently, a formic acid ester of cefamandole called cefamandole nafate was developed as a prodrug. The sodium salt of that ester is now marketed under the trade name of Mandol. The nafate ester of cefamandole is considered to be undesirable for topical ophthalmic administration because it is more unstable than the parent molecule and one of its degradation products, formic acid, is a potential source of ocular irritation.
When placed in an aqueous environment, cefamandole is subject to hydrolysis through several parallel mechanisms. The kinetics of that degradation have been thoroughly investigated in the prior art. For example, under the most favorable of conditions for an aqueous solution, cefamandole is degraded by 10% after 2.2 days at room temperature. This degradation is highly temperature dependent, meaning that a slight fluctuation in temperature above room temperature can accelerate the decomposition of an already very unstable molecule. It has been determined that in order to prepare a viable preparation for ophthalmic administration, the rate of decomposition must be decreased by at least three hundred fold.
Several mechanisms to stabilize cefamandole exist. One such method is the utilization of the principle of a sparingly water soluble salt. Theoretically, for a sparingly water soluble salt, only those molecules that are dissolved in water are susceptible to water attack, and as the solubilized drug is degraded more drug will dissolve to maintain the equilibrium solubility. The net effect is that the rate of degradation is dependent on the solubility of the molecule, and not on the total amount of drug. Thus, the reaction is said to be zero order. Mathematically, the rate of decomposition for a sparingly water soluble salt is given as: EQU (dc/dt)=-K(C)=-KS=K.sub.o,
where the rate of decomposition, dc/dt, is proportional to the concentration C in solution, which is the solubility, S; and K.sub.o is a zero order reaction constant.
For an aqueous ophthalmic preparation of 0.5% concentration to be stable for two years at room temperature, the K.sub.o must be be 6.84.times.10.sup.-7 gram per milliliter per day. Since it is known that the hydrolysis rate constant K is 0.046 per day at room temperature, it follows that the required solubility of the sparingly water soluble salt must be 1.48.times.10.sup.-5 gram per milliliter or less.
Penicillin V is a classic example of a compound susceptible to hydrolysis similar to the cephalosporins and having comparable stability problems. To overcome these stability problems, benzathine and hydrabamine salts prepared as the sparingly water soluble molecule are known in the art. See U.S. Pat. Nos. 2,812,326 and 2,627,491. The use of such benzathine or hydrabamine salts for cephalosporins to overcome this stability problem is not known in the prior art.